Influenza-induced tuft cell expansion alters ILC-mediated inflammation

Area of Science:

• Immunology
• Respiratory Medicine
• Cell Biology

Background:

• Tuft cells are key sentinels amplifying type 2 inflammation by activating type 2 innate lymphoid cells (ILC2s).
• Ectopic tuft cells emerge in the distal lung following severe injury, such as influenza infection.
• The role of these ectopic tuft cells in innate immunity post-lung injury remains largely unexplored.

Purpose of the Study:

• To investigate the function of ectopic tuft cells in shaping innate immunity after influenza-induced lung injury.
• To elucidate the regulatory interactions between tuft cells and innate lymphoid cells (ILCs) in the context of viral injury.
• To understand the contribution of tuft cells to inflammatory responses following viral injury and subsequent allergen challenge.

Main Methods:

• Utilized mouse models of influenza infection and lung injury.
• Generated tuft cell-deficient mice to assess their role in immune responses.
• Employed single-cell RNA sequencing (scRNA-seq) to analyze lung tissue transcriptomes.
• Performed subsequent aeroallergen challenge (Alternaria alternata) in injured mice.

Main Results:

• A reciprocal regulatory axis was identified where IFNγ restrains tuft cell differentiation, while ILC2s promote tuft cell expansion.
• Tuft cell-deficient mice showed reduced eosinophilic inflammation and increased ILC1 and ILC3 populations post-influenza injury.
• scRNA-seq revealed transcriptional signatures of type 1 pathway activation, type 2 suppression, and oxidative stress in infected lungs.
• In tuft cell-deficient mice, influenza injury followed by Alternaria alternata challenge led to neutrophilic and ILC3 expansion.

Conclusions:

• A distal airway tuft cell-ILC2 circuit plays a crucial role in maintaining immune balance after viral lung injury.
• This circuit influences the inflammatory milieu, impacting responses to both viral infections and aeroallergens.
• Ectopic tuft cells are critical regulators of innate immunity in the injured distal lung, modulating downstream immune cell populations and inflammatory pathways.